a study of nicotinamide with oral tetrahydrouridine and decitabine to treat high risk sickle cell disease

Conditions: Sickle Cell Disease

Summary: a randomized control trial in 20 subjects with sickle cell disease comparing oral thu-decitabine to nicotinamide and in combination (thu, decitabine and nicotinamide).

a randomized control trial comparing oral thu-decitabine to nicotinamide (1:1 randomization), and then comparing the effects of the combination of nicotinamide with thu-decitabine vs either treatment alone. treatment with each agent alone is for 12 weeks followed by the combination for a further 12 weeks. patients have the option to enter an extension phase of combination treatment for an additional 24 weeks (total of 48 weeks)

Eligibility criteria:
inclusion criteria: * age 18 years or older. * written informed consent provided by the subject before study entry. * confirmed sickle cell disease (scd) as determined by hemoglobin electrophoresis or liquid chromatography. * subject is in his/her steady state and not having any acute complication due to scd (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days). * weight at least 40kg * regular compliance with comprehensive care and previous therapy. * symptomatic scd is defined as having one of following, despite at least 6 months of hydroxyurea therapy, or refuse to take hydroxyurea for personal reasons: fetal hemoglobin \<0.5 g/dl, or 3 or more pain episodes per year requiring parenteral narcotics, or 1 or more acute chest syndrome episodes, or hemoglobin \<9 g/dl and absolute reticulocyte count \<250,000/mm3. exclusion criteria: * inability to give informed consent. * experienced severe sepsis or septic shock within the previous 12 weeks. * last hu dose was ingested within the previous 4 weeks. * currently pregnant or breast-feeding. * alanine aminotransferase (alt) ≥ 3 times the upper limit of normal or albumin \<2.0 mg/dl or direct (conjugated) bilirubin ≥ 1.5 mg/dl. * serum creatinine \>2.9 mg/dl and calculated creatinine clearance \<30 ml/min. * platelet count \>800 x 109/l. * absolute neutrophil count \<1.5 x 109/l. * female of active childbearing potential who is unwilling to use at least one of the two following forms of birth control: (i) not having heterosexual sexual contact beginning at the screening visit and continuing until 4 weeks after the last dose of decitabine or (ii) intrauterine device (iud). * sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of thu and decitabine. this requirement applies also to males who have had a successful vasectomy. * altered mental status or recurrent seizures requiring anti-seizure medications. * moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely. * concurrent diagnosis of malignancy including known myelodysplastic syndrome, leukemia, or an abnormal karyotype. * new york heart association (nyha) class iii/iv status. * eastern co-operative oncology group (ecog) performance status ≥3. * participant is on chronic transfusion therapy * known history of illicit drug or alcohol abuse within the past 12 months. * other experimental or investigational drug therapy in the past 28 days. * taking l-glutamine within the last 28 days * being positive for hiv infection